EP Patent No. 0145067 disclosed 2,2′-iminobisethanol derivatives. The compounds are antihypertensive agents. Among them nebivolol is racemic mixture of RSSS and its enantiomer of α,α′-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] and the structures of these isomers are shown below with stereochemical notation at each chiral centre.

Processes for preparations of nebivolol and related compounds were described in EP Patent No. 0145067 and EP Patent No. 0334429. According to the processes described in these patents, chromatographic separations are required for the separation of diastereomeric pairs at the intermediate stage or at the final stage. The chromatographic separations involve additional operations, additional expensive setup adding to the cost of production. U.S. Pat. No. 5,759,580 described the separation of (±)-[2R*[1S*, 5S*(S*)]]-α,α′-[Iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] hydrochloride (nebivolol hydrochloride) from the mixture of (±)-[2R*[1S*, 5S*(S*)]]±[2R*[1S*,5R*(R*)]]-α,α′-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol]. The yield of the nebivolol hydrochloride is extremely low (6.6%).
The PCT patent Application No. PCT/IN2004/000241 disclosed the isolation of racemic compound of formula A:
from the mixture of racemic compounds of formula B:
wherein P′ is a protecting group;by converting the mixture of isomers into their hydrochloric acid salts, subjecting fractional crystallization of desired isomers as hydrochloride salts and neutralizing to obtain the corresponding free bases of desired isomers.
The racemic compounds of formula A are key intermediates having desired stereo chemistry in the preparation of nebivolol. These intermediates are subjected to deprotection to obtain nebivolol.
We have found that a process for separating the desired racemic compound of formula A from the mixture of a pair of racemic compounds represented by formula B by suspending or dissolving the mixture of a pair of racemic compounds of formula B in a suitable solvent and then isolating crystals to obtain the racemic compound of formula A.
The process of the present invention enables us to isolate desired isomers of nebivolol intermediates from the mixture containing undesired and desired isomers just by suspending or dissolving the mixture containing undesired and desired isomers in a suitable solvent and crystallizing without the need for the expensive chromatographic separations. The present invention also avoids the lengthy process for this separation of converting the mixture of isomers into their hydrochloride salts, fractional crystallization of desired isomers and converting back into desired isomers in free base form.
Moreover, the process of the invention may be repeated any number of times very easily just by suspending or dissolving in a suitable solvent and isolating until we get desired isomeric purity.
Thus, the present invention provides extremely simple and commercially viable process for isolating desired racemic compound from mixture of isomers also containing undesired isomers.